100th Anniversary of Macromolecular Science Viewpoint: Biological Stimuli-Sensitive Polymer Prodrugs and Nanoparticles for Tumor-Specific Drug Delivery.

Abstract

The development of smart polymer vehicles to carry and release cytotoxic drugs to tumor tissues and cells while reducing the exposure of drugs in the blood and healthy organs is a highly challenging task with continuously growing interest from multiple fields, including polymer science, pharmaceutical science, nanotechnology, and clinical oncology. Inspired by the unique tumor microenvironment, such as mild acidity and overexpressed enzymes, functional polymer prodrugs and nanoparticles with reversible charge, detachable PEG shell, activatable ligand, and switchable size have been designed to enhance tumor deposition, tumor penetration, tumor cell uptake, and tumoral drug release. Utilizing biological signals inside tumor cells, such as acidic endo/lysosomal pH, elevated glutathione levels, and reactive oxygen species, responsive polymer prodrugs and nanoparticles with good extracellular stability but fast intracellular disintegration have been engineered for specific intracellular drug release. These biological stimuli-sensitive polymer prodrugs and nanoparticles have shown superior specificity and therapeutic efficacy to nonsensitive counterparts and, in certain cases, even clinically approved systems in varying tumor models. In this Viewpoint, design strategies and recent advances of biological stimuli-responsive polymer prodrugs and nanoparticles for tumor-specific drug delivery will be highlighted, and their challenges and future perspectives will be discussed.